Cone photoreceptors function under bright light conditions and are essential for color perception and vision with high temporal and spatial resolution. Remarkably, unlike rods, cones remain functional even in steady bright light and dark adapt rapidly. Both of these properties require rapid recycling of chromophore for regeneration of cone visual pigment. Biochemical studies and shortcomings of the canonical pigment epithelium pathway for chromophore recycling indicate the possible existence of a second, cone- specific chromophore pathway located in the retina and independent of the pigment epithelium. The function of such a pathway under physiological conditions, its role in photoreceptor physiology, and its regulation have not been investigated. We propose to use single-cell and whole retina recordings from mouse photoreceptors to characterize the physiological function of this novel visual cycle. Specifically, we will determine the ability of mammalian retina to promote pigment regeneration and dark adaptation in cones independently of the pigment epithelium. We will establish the role of the mammalian retina visual cycle in extending the dynamic range of cones during background adaptation and in accelerating the recovery of cone sensitivity during dark adaptation. We will determine whether the specificity of the mammalian retina visual cycle is based on the ability of cones, and not rods, to oxidize 11-cis retinol, recycled within the retina, into 11-cis retinal and use it for pigment regeneration. We will use available genetically modified mice and pharmacological tools to characterize key steps in the pathway and their modulation by chromophore-binding proteins expressed in the retina. Collectively, the experiments outlined in this proposal seek to establish the mechanisms that enable mammalian cones to function in rapidly varying light conditions, an essential property for the photoreceptors that mediate daytime vision. In addition to advancing the understanding of cone cell biology, our studies of the mammalian retina visual cycle have potential clinical implications. Mutations in the chromophore-binding proteins investigated in this study have been associated with multiple visual disorders including Stargardt disease, cone-rod dystrophy, and macular degeneration. No treatments currently exist for these disorders. Our experiments will lay the foundation for understanding how specific defects in the retina visual cycle produce cone-related retinal disorders, as well as for the development of new treatments targeting specifically the function of cones. PUBLIC HEALTH RELEVANCE: The experiments outlined in this proposal seek to establish the mechanisms that enable mammalian cones to function in bright light, an essential property for the photoreceptors that mediate daytime vision. These studies will help us understand the mechanisms that regulate mammalian cone function under normal and pathological conditions.